We propose to evaluate prospectively whether use of non-steroidal anti-inflammatory drugs (NSAIDs), and particularly selective COX-2 inhibitors, and statins reduces the risk of Parkinson's disease (PD). A key role of inflammatory and oxidative processes in the degeneration of dopaminergic neurons in PD is supported by experimental and postmortem studies. Further, preliminary findings from prospective investigations suggest that regular use of NSAIDs is associated with lower risk. To address these hypotheses, we propose to extend to the year 2008 the follow-up of PD in the Nurses'Health Study (NHS), the Health Professional Follow-up Study (HPFS), and the Cancer Prevention Study-ll Nutrition (CPS-IIN), three well-established cohorts that collectively comprise a population of over 335,000 individuals. Participants in these cohorts have provided detailed information on use of NSAIDs, diet, lifestyle, and medical history over the past 14 to 24 years;50,843 participants have also provided blood samples that have been stored for future analyses. The past occurrence of incident PD in these cohorts has already been documented or is in progress - 415 cases have been confirmed in the NHS and HPFS, and approximately 550 cases are being confirmed in the CPS-IIN cohort. By extending the follow-up we expect to confirm 988 new incident cases. We will be able for the first time to test whether users of selective COX-2 inhibitors and statins (neither was included in previous follow-up) have a lower risk of PD, and to examine dose-response relationships, the effects of duration of use or time since use, differences between individual NSAIDs, and possible interaction with other risk factors, including exposure to pesticides that we have shown in preliminary analyses to be associated with an increased risk of PD and to interact with NSAIDs use. Blood samples collected at different time intervals before the diagnosis will be available. Using these samples, we will examine the novel hypothesis that elevations in plasma levels of alpha-synuclein precede the onset of PD. Lastly, the proposed project will establish a unique resource that will be readily available for future studies on the etiology of PD.